Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

Ma G ，Yang J ，Wang X ，Xia E ，Yu J ，Zhang M ，Hu Y ，Ma S ，Zhou X ，Fan Q ，Han Y ，Wang J ... -  《Scientific Reports》

Two-sample Mendelian randomization analysis of causal relationship between eczema and autoimmune diseases.

Chen C ，Yan S ，Wan B ，Yu Y ，Zeng J ，Tan L ，Lu J ... -  《-》

Primary biliary cholangitis has causal effects on systemic rheumatic diseases: a Mendelian randomization study.

An association has been observed between primary biliary cholangitis (PBC) and systemic rheumatic diseases (SRDs) in observational studies, however the exact causal link remains unclear. We aimed to evaluate the causal effects of PBC on SRDs through Mendelian randomization (MR) analysis. The genome-wide association study (GWAS) summary data were obtained from MRC IEU OpenGWAS and FinnGen databases. Independent genetic variants for PBC were selected as instrumental variables. Inverse variance weighted was used as the main approach to evaluate the causal effects of PBC on Sjögren syndrome (SS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD) and polymyositis (PM). Horizontal pleiotropy and heterogeneity were measured by MR‒Egger intercept test and Cochran's Q value, respectively. PBC had causal effects on SS (OR = 1.177, P = 8.02e-09), RA (OR = 1.071, P = 9.80e-04), SLE (OR = 1.447, P = 1.04e-09), SSc (OR = 1.399, P = 2.52e-04), MCTD (OR = 1.306, P = 4.92e-14), and PM (OR = 1.416, P = 1.16e-04). Based on the MR‒Egger intercept tests, horizontal pleiotropy was absent (all P values > 0.05). The robustness of our results was further enhanced by the leave-one-out method. Our research has provided new insights into PBC and SRDs, indicating casual effects on various SRDs.

Zhang HP ，Zhou Z ，Chen K ，Xiong LF ，Wu J ，Jin L ... -  《BMC GASTROENTEROLOGY》

Genetic link between primary biliary cholangitis and connective tissue diseases in European populations: A two-sample Mendelian randomization study.

An association between primary biliary cholangitis (PBC) and connective tissue diseases (CTDs) [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), systemic sclerosis (SSc)] has been found in observational studies. However, the direction causality is unclear. The aim of this study was to assess the causality between PBC and CTDs and to promote early screening, pre-emptive therapy, and accurate stratification. A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between PBC [Genome-Wide Association Study (GWAS) meta-analysis, 8021 cases/16498 controls], and SLE (GWAS meta-analysis, 8021 cases/16489 controls), RA(FinnGen, 6236 cases/14727 controls), SS(FinnGen, 2495 cases/365533 controls), SSc (FinnGen, 302 cases/213145 controls). Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by four sensitivity analyses to assess the robustness of the results. The IVW revealed that genetically predicted PBC increased the risk of SLE [odd's ratio (OR) = 1.43, 95% confidence interval (CI) 1.30-1.58, P < 0.001]), RA (OR = 1.09, 95%CI1.04-1.14, P<0.001), and SS (OR = 1.18, 95%CI1.12-1.24, P<0.001), but not that of SSc. In addition, no association was observed between CTDs as an exposure and PBC. Sensitivity analyses did not reveal horizontal pleiotropy. Our study provided new genetic evidence for a causal relationship between PBC and CTDs. PBC increased the risk of SLE, RA, and SS. Our findings highlighted the importance of active screening and intervention for CTDs in patients with PBC.

Liu Z ，Shao Y ，Duan X 《PLoS One》

Causal association between autoimmune liver disease and Sjögren's syndrome: A Mendelian randomization study.

Observational studies have found an association between autoimmune liver disease (AILD) and Sjögren's syndrome (SS). However, the causal relationship between the two remains unknown. Clinical guidelines indicate that the coexistence of AILD with other autoimmune diseases may impact prognosis and quality of life; hence, early recognition and management of extrahepatic autoimmune diseases is particularly crucial. Against this backdrop, this study aimed to utilize Mendelian randomization (MR) methods to investigate the potential causal relationship between AILD and SS. We extracted summary statistics on AILD and SS from publicly available genome-wide association studies (GWAS) databases to identify appropriate instrumental variables (IVs). The inverse-variance weighted (IVW) method was utilized as the primary approach, with the weighted median (WM) method and MR-Egger method employed as supplementary methods to evaluate the potential causal relationship between the two conditions. Sensitivity analyses, including Cochran's Q test, MR-polynomial residuals and outliers (MR-PRESSO), MR-Egger intercept test, and the leave-one-out test, were performed to assess the stability of the results. The MR study results indicate a significant causal relationship between PBC and PSC with the risk of SS in the European population (IVW: odds ratio [OR] = 1.155, 95% confidence interval [CI]: 1.092-1.222, p < .001; IVW: OR = 1.162, 95% CI: 1.051-1.284, p = .003). A series of sensitivity analyses have confirmed the reliability of the results. Our study indicates that the presence of both PBC and PSC increases the susceptibility to SS. However, no reliable causal relationship was found between SS and the risk of PBC or PSC. These findings contribute to elucidating the potential pathogenic mechanisms of the disease and are of significant importance for the management of patients with PBC and PSC.

Li Y ，Wang J ，Jiang H ，Zhang J ，Qi J ，Jiang Z ，Chen L ，Ying Z ... -  《-》